JP7361131B2 - Use of iminostilbene in the prevention and treatment of cardiac and cerebral ischemia-reperfusion injuries - Google Patents
Use of iminostilbene in the prevention and treatment of cardiac and cerebral ischemia-reperfusion injuries Download PDFInfo
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Description
本発明は、心臓・脳血管疾患の分野に属し、より具体的には、本発明は、イミノスチルベン（Ｉｍｉｎｏｓｔｉｌｂｅｎｅ）の心臓・脳虚血再灌流損傷の予防・治療における使用に関する。 The present invention belongs to the field of cardiac and cerebrovascular diseases, and more specifically, the present invention relates to the use of iminostilbene in the prevention and treatment of cardiac and cerebral ischemia-reperfusion injury.
社会の高齢化と都市化の加速に伴い、住民の不健康な生活様式が多くなり、心臓・脳血管疾患の危険因子が普遍的に出現しており、多発性疾患を引き起こす。血栓、血管破裂などの原因による心臓・脳虚血性疾患は非常によく見られ、その処置は一般的に抗血栓によるうっ血除去治療を主とする。虚血となった心筋と脳は血液再灌流を回復した後、あらゆる面で損傷がさらに悪化する現象、すなわち虚血再灌流損傷が発生し、虚血性疾患を治療する大きな障害となり、再灌流損傷の起因はまだ完全に明確ではなく、フリーラジカルの蓄積、細胞カルシウムの過負荷、膜損傷などはすべてその発生の原因である可能性があり、現在治療の方法と薬物はまだ限られており、しかも効果も高める余地がある。 With the aging of society and the acceleration of urbanization, the population's unhealthy lifestyle is becoming more common, and risk factors for cardiovascular and cerebrovascular diseases have become commonplace, causing multimorbidity. Cardiac and cerebral ischemic diseases caused by thrombosis, vascular rupture, etc. are very common, and their treatment generally consists of anti-thrombotic decongestion therapy. After the ischemic myocardium and brain recover blood reperfusion, a phenomenon in which the damage is further aggravated in all aspects, that is, ischemia-reperfusion injury occurs, which becomes a major obstacle in the treatment of ischemic diseases, and reperfusion injury. The cause is still not completely clear, free radical accumulation, cellular calcium overload, membrane damage, etc. may all be responsible for its occurrence, and current treatment methods and drugs are still limited. Moreover, there is room to improve its effectiveness.
イミノスチルベンＩｍｉｎｏｓｔｉｌｂｅｎｅ（ＩＳＢ）はジベンザゼピン系化合物であり、現在知られている医薬用途は抗肝炎及び抗てんかん薬であるカルバマゼピン合成中間体のみであり、また、この化合物は排ガス触媒及びトランジスタにのみ応用されている。心臓・脳虚血再灌流損傷の予防・治療に応用した報告はまだない。 Iminostilbene (ISB) is a dibenzazepine compound, and its currently known medical use is only as a synthetic intermediate of carbamazepine, an antihepatitis and antiepileptic drug, and this compound is only applied to exhaust gas catalysts and transistors. ing. There are no reports yet on its application to the prevention or treatment of cardiac or cerebral ischemia-reperfusion injury.
新規な心臓・脳虚血再灌流損傷医薬品を開発するために、研究したところ、イミノスチルベンが心筋及び脳虚血に対して保護作用を有することを見出し、イミノスチルベンが上記保護作用を発揮する作用メカニズムをさらに研究し、イミノスチルベンの心臓・脳血管疾患の治療における使用のために実験資料や理論的根拠を提供する。 In order to develop a new cardiac/cerebral ischemia-reperfusion injury drug, we conducted research and found that iminostilbene has a protective effect against myocardial and cerebral ischemia. To further study the mechanism and provide experimental materials and rationale for the use of iminostilbene in the treatment of cardiovascular and cerebrovascular diseases.
一態様では、本出願は、心臓・脳血管疾患を治療する医薬品の製造におけるイミノスチルベンの使用を提供する。 In one aspect, the application provides the use of iminostilbene in the manufacture of a medicament for treating cardiovascular and cerebrovascular diseases.
さらに、前記心臓・脳血管疾患は虚血再灌流損傷である。 Further, the cardiac/cerebrovascular disease is ischemia-reperfusion injury.
さらに、前記心臓・脳血管疾患は脳虚血再灌流損傷である。 Further, the cardiac/cerebrovascular disease is cerebral ischemia-reperfusion injury.
さらに、イミノスチルベンは脳梗塞面積を減少させる。 Additionally, iminostilbene reduces cerebral infarction area.
さらに、前記心臓・脳血管疾患は心筋虚血再灌流損傷である。 Further, the cardiac/cerebrovascular disease is myocardial ischemia-reperfusion injury.
さらに、前記心臓・脳血管疾患は虚血性心疾患である。 Furthermore, the cardiac/cerebrovascular disease is ischemic heart disease.
さらに、イミノスチルベンは心筋梗塞面積を減少させ、及び／又はＬＤＨ、ＡＳＴ和ＣＫレベルを低減させ、及び／又は炎症性因子を低減させ、及び／又は心筋アポトーシスを減少させる。 Furthermore, iminostilbene reduces myocardial infarction area, and/or reduces LDH, AST and CK levels, and/or reduces inflammatory factors, and/or reduces myocardial apoptosis.
別の態様では、本出願は、心筋保護薬の製造における、イミノスチルベンの使用を提供する。 In another aspect, the application provides the use of iminostilbene in the manufacture of a cardioplegic agent.
さらに、前記医薬品の最小単位に含まれる活性成分であるイミノスチルベンの量が、０．５～１０ｍｇである。 Furthermore, the amount of iminostilbene, which is an active ingredient, contained in the smallest unit of the pharmaceutical is 0.5 to 10 mg.
さらに、前記医薬品は錠剤又は水溶性注射剤である。 Further, the pharmaceutical product is a tablet or a water-soluble injection.
別の態様では、本発明は、イミノスチルベンを有効成分として含む心臓・脳虚血再灌流損傷を治療する医薬品を提供する。 In another aspect, the present invention provides a medicament for treating cardiac and cerebral ischemia-reperfusion injury comprising iminostilbene as an active ingredient.
さらに、イミノスチルベンは唯一な有効成分である。 Additionally, iminostilbene is the only active ingredient.
本発明の前記心臓・脳血管疾患は、様々な血栓、血液レオロジー、血管の原因による疾患を含み、血栓、梗塞、血管破裂などを含むが、これらに限定されない。 The cardiac/cerebrovascular diseases of the present invention include diseases due to various thrombotic, blood rheological, and vascular causes, including, but not limited to, thrombosis, infarction, vascular rupture, and the like.
本発明の前記最小単位は、剤形に応じて、１錠、１カプセル、１袋の顆粒、又は１本の注射剤などを含むが、これらに限定されない。 The minimum unit of the present invention includes, but is not limited to, one tablet, one capsule, one bag of granules, one injection, etc., depending on the dosage form.
本発明の前記医薬品は、経口投与形態及び胃腸外投与形態の様々な剤形を含む、臨床的に許容される任意の剤形であり得る。経口に用いる場合、錠剤、カプセル、ソフトカプセル、経口液、シロップ、顆粒、滴丸、口腔内崩壊錠、徐放錠、徐放カプセル、放出制御錠、放出制御カプセルであってもよく、胃腸外投与経路に用いる場合、水溶性注射剤、凍結乾燥粉末注射剤、無菌粉末注射剤、輸液であってもよい。 The medicament of the invention may be in any clinically acceptable dosage form, including a variety of oral and parenteral dosage forms. When used orally, it may be a tablet, capsule, soft capsule, oral liquid, syrup, granule, drop pill, orally disintegrating tablet, sustained release tablet, sustained release capsule, controlled release tablet, controlled release capsule, and for parenteral administration. When used by route, it may be a water-soluble injection, a lyophilized powder injection, a sterile powder injection, or an infusion.
医薬品中の薬学的に許容される担体又は賦形剤には、充填剤、バインダ、潤滑剤、崩壊剤、溶解助剤、界面活性剤、吸着担体、溶剤、酸化防止剤、共溶媒、吸着剤、浸透圧調節剤、ｐＨ調整剤が含まれるが、これらに限定されない。 Pharmaceutically acceptable carriers or excipients in pharmaceuticals include fillers, binders, lubricants, disintegrants, solubilizers, surfactants, adsorption carriers, solvents, antioxidants, cosolvents, and adsorbents. , osmotic pressure regulators, and pH regulators, but are not limited to these.
医薬品には、スーパーオキシドジスムターゼ、ビタミンＣ、ビタミンＥ、コエンザイムＱ１０、エダラボン、抗炎症薬、トウサンカ抽出物、丹参滴丸などを含むが、これらに限定されない、心臓・脳血管疾患を治療するその他の既知の中西薬物を含めることができ、又は本出願の薬物はこれらの漢方薬や西洋薬と併用してもよい。 Medicinal products include, but are not limited to, superoxide dismutase, vitamin C, vitamin E, coenzyme Q10, edaravone, anti-inflammatory drugs, Tosanka extract, Danshen drops, etc., and other drugs to treat cardiovascular and cerebrovascular diseases. Known Chinese and Western drugs may be included, or the drugs of the present application may be used in combination with these Chinese and Western medicines.
本発明の剤形は、医薬製剤プロセスにおいて当業者に公知の慣用的に使用されている任意の方法を用いて製造することができる。例えば、本発明の錠剤は、当技術分野で公知の適切な方法を用いて、造粒して乾燥させ、主剤、賦形剤及びバインダなどをふるい分け、得た混合物に潤滑剤などを加えて混合し、錠剤を形成することができる。造粒は、湿式造粒、乾式造粒や加熱造粒のような、当技術分野で公知の任意の適切な方法によって行うことができる。適切な非限定的な例としては、高速撹拌造粒機、流動造粒乾燥機、押出造粒機、又はドラムプレスを使用したような造粒方法が含まれる。さらに、例えば乾燥及びふるい分けの方法は造粒のニーズに応じて行うことができる。主剤、賦形剤、バインダ、潤滑剤などの混合物は直接錠剤に形成することもできる。フィルムコーティングが必要な場合、当技術分野で知られているフィルムコーティング装置のいずれかを使用することができ、フィルムコーティングマトリックスとして好適な例としては、糖衣系、親水性フィルムコーティング系、腸溶性フィルムコーティング系、及び徐放性フィルムコーティング系が含まれる。
The dosage forms of the present invention can be manufactured using any commonly used method known to those skilled in the art in pharmaceutical formulation processes. For example, the tablets of the present invention can be prepared by granulating and drying the tablets using an appropriate method known in the art, sieving out the base ingredient, excipients, binders, etc., adding a lubricant, etc. to the resulting mixture, and mixing. and can be formed into tablets. Granulation can be carried out by any suitable method known in the art, such as wet granulation, dry granulation or heat granulation. Suitable non-limiting examples include granulation methods such as using a high speed agitation granulator, a fluidized granulator dryer, an extrusion granulator, or a drum press. Furthermore, for example drying and sieving methods can be performed depending on the granulation needs. A mixture of base ingredients, excipients, binders, lubricants, etc. can also be directly formed into tablets. If film coating is required, any film coating equipment known in the art can be used; suitable examples of film coating matrices include sugar coating systems, hydrophilic film coating systems, enteric films. coating systems, and sustained release film coating systems.
以下、特定の実施例を参照して本発明をさらに詳細に説明するが、本発明のさらなる制限を構成するものではない。 The invention will now be explained in more detail with reference to specific examples, which do not constitute further limitations of the invention.
実施例１
ＩＳＢによる心筋虚血再灌流損傷ラットの心筋梗塞面積の検出
正常群、モデル群、ＩＳＢ低用量群（０．６２５ｍｇ／ｋｇ）、ＩＳＢ高用量群（１．２５ｍｇ／ｋｇ）、ジルチアゼム塩酸塩群（１６ｍｇ／ｋｇ）の５群に動物をランダムに分けた。ＩＳＢの各用量群とジルチアゼム塩酸塩群は術前に３日間連続して胃内投与した。実験動物を３０ｍｉｎ虚血、２４ｈ再灌流後、ラットを麻酔し、開胸して心臓を採取し、生理食塩水に入れて洗浄し、－８０Ｃで７ｍｉｎ放置した後に取り出し、心尖から結紮線方向に心臓を１～２ｍｍ厚さで横切断した薄片５～７枚とした。２％ＴＴＣ溶液に入れ、３７℃の水浴で１２ｍｉｎ加熱し、中性ホルマリンに入れて固定し、室温で一晩静置し、翌日、実体顕微鏡で撮影した。心臓切片の梗塞領域は灰白色、切片の非梗塞領域は赤色であり、Ｉｍａｇｅ－Ｐｒｏ Ｐｌｕｓソフトウェアを用いて梗塞を検出し、心筋梗塞率＝梗塞領域面積／心筋切片領域総面積×１００％であった。
結果を図１に示し、図に示すように、Ｓｈａｍ群は梗塞面積がなく、Ｉ／Ｒ群ラットはＳｈａｍ群と比較して心筋梗塞面積が有意に増加した。Ｉ／Ｒ群と比べ、Ｉ／Ｒ＋ＩＳＢ（０．６２５、１．２５ｍｇ／ｋｇ）は心筋組織梗塞面積を有意に改善した。
Example 1
Detection of myocardial infarction area in rats with myocardial ischemia-reperfusion injury caused by ISB Normal group, model group, ISB low dose group (0.625 mg/kg), ISB high dose group (1.25 mg/kg), diltiazem hydrochloride group ( Animals were randomly divided into 5 groups (16 mg/kg). Each dose group of ISB and the diltiazem hydrochloride group were administered intragastrically for 3 consecutive days before surgery. After subjecting the experimental animal to ischemia for 30 min and reperfusion for 24 h, the rat was anesthetized, the heart was harvested through thoracotomy, washed in physiological saline, left at -80C for 7 min, taken out, and inserted from the apex of the heart in the direction of the ligation line. The heart was cut transversely into 5 to 7 slices with a thickness of 1 to 2 mm. It was placed in a 2% TTC solution, heated for 12 minutes in a 37°C water bath, fixed in neutral formalin, left to stand overnight at room temperature, and photographed using a stereomicroscope the next day. The infarcted area of the heart section was grayish white, and the non-infarcted area of the section was red. Infarction was detected using Image-Pro Plus software, and the myocardial infarction rate = infarct area area / total area of myocardial section area x 100%. .
The results are shown in FIG. 1, and as shown in the figure, the Sham group had no infarcted area, and the I/R group rats had a significantly increased myocardial infarction area compared to the Sham group. Compared with the I/R group, I/R+ISB (0.625, 1.25 mg/kg) significantly improved myocardial tissue infarction area.
実施例２
心筋虚血再灌流損傷ラットの心臓組織の病理学的変化へのＩＳＢの影響
実験終了後、開胸して心臓を採取し、パラホルムアルデヒドで固定し、パラフィン切片、ＨＥ染色を行った。
図２に示した結果のように、偽手術群では、心筋細胞の形態構造が正常であり、心筋細胞膜が完全であり、組織間隙が正常であり、炎症性細胞浸潤がなく、心筋繊維の配列は規則的であった。モデル群では、心筋細胞の組織間隙が増大し、その間に浮腫が出現し、好中球浸潤が明らかで、心筋繊維の向きがはっきりしておらず、一部の領域では心筋繊維が断裂し、心内膜壊死が認められた。ＩＳＢ群では、細胞間隙がモデル群より軽減し、炎症性細胞浸潤がある程度減少し、このことから、ＩＳＢは心筋組織損傷程度を明らかに改善できることを示した。
Example 2
Effect of ISB on pathological changes in cardiac tissue of rats with myocardial ischemia-reperfusion injury After the experiment, the heart was collected through thoracotomy, fixed with paraformaldehyde, paraffin sectioned, and HE stained.
As shown in Figure 2, in the sham surgery group, the morphological structure of myocardial cells was normal, the myocardial cell membrane was intact, the interstitial space was normal, there was no inflammatory cell infiltration, and the arrangement of myocardial fibers was normal. was regular. In the model group, the interstitial space of myocardial cells increased, edema appeared between them, neutrophil infiltration was obvious, the orientation of myocardial fibers was unclear, and myocardial fibers were torn in some areas. Endocardial necrosis was observed. In the ISB group, the intercellular space was reduced compared to the model group, and inflammatory cell infiltration was reduced to some extent, indicating that ISB can clearly improve the degree of myocardial tissue damage.
実施例３
心筋虚血再灌流損傷ラットの心臓機能へのＩＳＢの影響
７日再灌流後、イソフルランで動物を麻酔し、ＶｉｓｕａｌＳｏｎｉｃｓ Ｖｅｖｏ７７０超音波高分解能小動物超音波画像システムを用いて各群のラットの心臓構造と機能を評価し、主要な検出指標はＬＶＥＦとＬＶＦＳであった。
図３に示すように、偽手術ｓｈａｍ群と比較して、ＩＲモデル群では、ＥＦ、ＦＳが有意に低下したが、ＩＳＢはＥＦとＦＳを有意に増加し、心臓機能を改善した。
Example 3
Effect of ISB on cardiac function in rats with myocardial ischemia-reperfusion injury After 7 days of reperfusion, the animals were anesthetized with isoflurane, and the cardiac structures of rats in each group were determined using a VisualSonics Vevo770 ultrasound high-resolution small animal ultrasound imaging system. Function was evaluated, and the main detection indicators were LVEF and LVFS.
As shown in Figure 3, compared with the sham surgery sham group, EF and FS significantly decreased in the IR model group, but ISB significantly increased EF and FS and improved cardiac function.
実施例４
ＩＳＢによる心筋虚血再灌流損傷ラットの心筋酵素の検出
実験動物を２４時間再灌流し、３％ペントバルビタールナトリウム溶液（３０ｍｇ／ｋｇ）で麻酔してラットの腹部大動脈から採血し、３５００ｒｐｍで１５ｍｉｎ遠心分離し、血清を分離し、全自動生化学計を用いて心筋酵素ＣＫ、ＬＤＨ、ＡＳＴの活性を測定した。
図４に示すように、Ｉ／Ｒ群は、Ｓｈａｍ群と比較して血清中ＬＤＨ、ＣＫ、ＡＳＴ活性が有意に上昇し、このことから、心筋虚血再灌流時に組織が損傷を受けたことを示し、ＩＳＢはＩ／Ｒ群と比較してＬＤＨ、ＣＫ、ＡＳＴのリークを有意に低下させた。
Example 4
Detection of myocardial enzymes in rats with myocardial ischemia-reperfusion injury caused by ISB Experimental animals were reperfused for 24 hours, anesthetized with 3% sodium pentobarbital solution (30 mg/kg), blood was collected from the abdominal aorta of the rat, and centrifuged at 3500 rpm for 15 min. The serum was separated, and the activities of cardiac enzymes CK, LDH, and AST were measured using a fully automatic biochemistry meter.
As shown in Figure 4, serum LDH, CK, and AST activities significantly increased in the I/R group compared to the Sham group, indicating that the tissue was damaged during myocardial ischemia-reperfusion. , and ISB significantly reduced LDH, CK, and AST leaks compared to the I/R group.
実施例５
ＩＳＢによるラット心筋虚血再灌流損傷の炎症因子ＩＬ－１０及びＩＬ－６の検出
実験動物を２４時間再灌流し、３％ペントバルビタールナトリウム溶液（３０ｍｇ／ｋｇ）でラット麻酔して腹部大動脈から採血し、３５００ｒｐｍで１５ｍｉｎ遠心分離し、血清を分離し、キットの取り扱い書に従って血清ＩＬ－１０、ＩＬ－６の含有量を検出し、そしてマイクロプレートリーダによる４５０ｎｍ波長測定値を採用して、検量線によりサンプル血清中のＩＬ－１０、ＩＬ－６の含有量を計算した。
図５に示すように、偽手術ｓｈａｍ群と比較して、ラット脳虚血再灌流損傷の場合、血漿ＴＮＦαとＩＬ－６の含有量は有意に上昇した（Ｐ＜０．０１）。ＴＡＢ（５、１０ｍｇ／ｋｇ）はモデル群と比較してＴＮＦαとＩＬ－６の含有量を有意に低下させた（Ｐ＜０．０５）。
Example 5
Detection of inflammatory factors IL-10 and IL-6 in rat myocardial ischemia-reperfusion injury caused by ISB Experimental animals were reperfused for 24 hours, rats were anesthetized with 3% pentobarbital sodium solution (30 mg/kg), and blood was collected from the abdominal aorta. The serum was separated by centrifugation at 3500 rpm for 15 min, and the content of serum IL-10 and IL-6 was detected according to the instruction manual of the kit, and the calibration curve was calculated using the 450 nm wavelength measurement value using a microplate reader. The contents of IL-10 and IL-6 in the sample serum were calculated.
As shown in FIG. 5, compared with the sham-operated sham group, the contents of plasma TNFα and IL-6 were significantly increased in rat cerebral ischemia-reperfusion injury (P<0.01). TAB (5, 10 mg/kg) significantly reduced the content of TNFα and IL-6 compared to the model group (P<0.05).
実施例６
ラット心筋虚血再灌流損傷の心筋アポトーシスへのＩＳＢの影響
実験終了後、開胸して心臓を採取し、パラホルムアルデヒドで固定し、パラフィン切片、ＴＵＮＥＬ染色を行った。
図６に示すように、偽手術ｓｈａｍ群ではＴＵＮＥＬ陽性細胞はほとんど認められなかったが、ＩＲラット心臓ではＴＵＮＥＬ陽性心筋細胞は多く認められ、ＩＳＢ投与群ではＴＵＮＥＬ陽性心筋細胞は有意に減少した。
Example 6
Effect of ISB on myocardial apoptosis following rat myocardial ischemia-reperfusion injury After the experiment, the heart was collected through thoracotomy, fixed with paraformaldehyde, paraffin sectioned, and TUNEL stained.
As shown in FIG. 6, almost no TUNEL-positive cells were observed in the sham-operated sham group, but many TUNEL-positive cardiomyocytes were observed in the IR rat hearts, and the number of TUNEL-positive cardiomyocytes decreased significantly in the ISB administration group.
実施例７
ラット脳虚血再灌流損傷の脳梗塞面積へのＩＳＢの影響
正常群、モデル群、ＩＳＢ低用量群（５ｍｇ／ｋｇ）、ＩＳＢ高用量群（１０ｍｇ／ｋｇ）、アスピリン群（１０ｍｇ／ｋｇ）の５群に動物をランダムに分けた。ＩＳＢ各用量群とアスピリン群は術前に３日間連続して胃内投与した。実験動物を３０ｍｉｎ虚血、２４ｈ再灌流後、ラットを麻酔し、脳を採取し、生理食塩水に入れて洗浄し、－８０Ｃで７ｍｉｎ放置した後に取り出し、脳を１～２ｍｍ厚さで横切断した薄片５～７枚とした。１％ＴＴＣ溶液に入れ、３７℃の水浴で１２ｍｉｎ加熱し、中性ホルマリンに入れて固定し、室温で一晩静置し、翌日、実体顕微鏡で撮影した。脳切片の梗塞領域は灰白色、切片の非梗塞領域は赤色であり、Ｉｍａｇｅ－Ｐｒｏ Ｐｌｕｓソフトウェアを用いて梗塞を検出し、梗塞率＝梗塞領域面積／心筋切片領域総面積×１００％であった。
図７に示すように、偽手術ｓｈａｍ群と比較して、ＭＣＡＯによるモデル作成後、ラットの脳梗塞面積は有意に増加し、ＩＳＢ投与３日後に脳梗塞面積は有意に減少した。
Example 7
Effect of ISB on cerebral infarction area in rat cerebral ischemia-reperfusion injury Normal group, model group, ISB low dose group (5 mg/kg), ISB high dose group (10 mg/kg), aspirin group (10 mg/kg) Animals were randomly divided into 5 groups. Each dose group of ISB and the aspirin group were administered intragastrically for 3 consecutive days before surgery. After subjecting the experimental animal to ischemia for 30 min and reperfusion for 24 h, the rat was anesthetized, the brain was collected, washed in physiological saline, left at -80C for 7 min, then removed, and the brain was transected to a thickness of 1 to 2 mm. 5 to 7 thin slices were prepared. It was placed in a 1% TTC solution, heated for 12 minutes in a 37°C water bath, fixed in neutral formalin, left to stand overnight at room temperature, and photographed using a stereomicroscope the next day. The infarcted area of the brain section was grayish white, and the non-infarcted area of the section was red. Infarction was detected using Image-Pro Plus software, and the infarction rate = infarcted area area/total area of myocardial section area x 100%.
As shown in FIG. 7, compared to the sham-operated sham group, the cerebral infarction area of rats significantly increased after model creation using MCAO, and the cerebral infarction area significantly decreased 3 days after ISB administration.
明らかに、本発明の上記実施例は、本発明を明確に説明するための例示に過ぎず、本発明の実施形態を限定するものではない。当業者にとっては、上記した説明に基づいて、他の異なる形態の変更又は変更が行われてもよい。ここでは、全ての実施形態を網羅する必要はなく、また、不可能なことである。本発明の主旨から導出する自明な変化又は変動は、本発明の特許範囲に含まれるものとする。 Obviously, the above embodiments of the invention are merely illustrative to clearly explain the invention, and are not intended to limit the embodiments of the invention. Other different forms of modifications or variations may occur to those skilled in the art based on the above description. It is not necessary or possible to cover all embodiments here. Obvious changes or variations derived from the spirit of the invention shall be included within the patentable scope of the invention.
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